This proposal is the competing renewal of our ongoing work into the neural substrates of anxiety. In a natural progression of this work, we now propose to test key aspects of a neural circuit model for anxiety disorders. We will use BOLD fMRI in conjunction with emotion processing tasks to compare healthy controls subjects (HC) to patients with panic disorder (PD) and generalized anxiety disorder (GAD), who will be studied before and after cognitive behavioral treatment (CBT). This proposal brings together methods and approaches from behavioral and cognitive neuroscience, functional neuroimaging imaging, and psychological clinical therapeutics to outline a series of studies with the long-term objective of delineating the neural substrates of anxiety disorders. The principal objective of this competitive renewal is to build on the applicants' previously accomplished work in non-clinical individuals with anxiety proneness and apply this to patients with anxiety disorders with the following specific aims: (1) To develop a basic systems neuroscience endophenotype for anxiety disorders. Based on our prior work, we hypothesize that, compared to healthy controls (HC), patients with GAD or PD will show increased activation of the anterior insula during various types of emotion processing that engage interoceptive systems. Moreover, we hypothesize that there is less functional coupling between the insular cortex and both the amygdala and the medial prefrontal cortex (mPFC) in patients with anxiety disorders. (2) To evaluate effects of CBT on the neural systems hypothesized to be dysfunctional in patients with anxiety disorders. We expect that successful treatment will be associated with attenuation of insular cortex activity and increased coupling between insula and both amygdala and mPFC, respectively. In the case of GAD, we also expect to see a reduction in task-related dorsolateral prefrontal cortex (DLPFC) activity. Anxiety disorders are early onset, prevalent, serious conditions that impact adversely on individual and societal functioning. Improved understanding of the neural circuitry of anxiety disorders will inform diagnostic conceptualizations and enable the more directed development and testing of novel therapies that are based on a more thorough understanding of pathophysiology, thereby conveying new therapeutic options to the many patients with anxiety disorders for whom existing treatments are inadequate. [unreadable] [unreadable] [unreadable]